Band 26, Heft 11-12

Neuroblastoma are the most common extracranial solid tumor of childhood. It is a malignancy derived from embryonic neural crest cells of the peripheral sympathetic nervous system that demonstrates remarkably heterogenous clinical and biological behavior ranging from spontaneous regression to inexorable progression with fatal outcomes. Various imaging modalities, including plain radiograph, ultrasound, computed tomography (CT), magnetic resonance imaging, bone scintigraphy, metaiodobenzylguanidine scintigraphy, and positron emission tomography/CT have been used to diagnose primary and metastatic neuroblastoma. In this article, we review the application of various imaging modalities to better define and recognize their role in the diagnosis and follow-up of neuroblastoma.

Objective: To determine a levothyroxine (T4) dose recommendation for the treatment of autoimmune thyroiditis (AIT)-induced hypothyroidism. Methods: T4 doses in 75 children and adolescents with newly diagnosed AIT were prospectively collected and compared to T4 doses of patients with congenital hypothyroidism (CH, n=22). Results: Sixty-four patients with AIT and 22 patients with CH were included in the analysis. The thyroid-stimulating hormone declined significantly from 25.8±50.1 to 2.1±1.5 μIU/mL (AIT group; p<0.01) and from 338.7±380.7 to 1.9±1.6 μIU/mL (CH group; p<0.01). The required T4 dose for patients with AIT was 1.5±0.5 μg/kg per day (≥6 to <10 years: 2.0±0.4 μg T4/kg per day; ≥10 to <12 years: 1.6±0.4 μg T4/kg per day; ≥12 to <14 years: 1.5±0.6 μg T4/kg per day; ≥14 years: 1.4±0.6 μg T4/kg per day). It deviated significantly from the CH patients’ mean T4 dose of 2.8±0.7 μg T4/kg per day, p<0.01. CH patients with athyreosis required an average dose of 3.1±0.5 μg T4/kg per day; patients with ectopia, 2.6±0.7 μg T4/kg per day; and patients with dyshormonogenesis, 2.5±0.6 μg T4/kg per day. Conclusion: Juvenile patients with AIT require significantly lower T4 doses than patients with CH.

Aim: To investigate the influence of overt hyperthyroidism and euthyroid congenital hypothyroidism on fasting glucagon-like peptide-1 (GLP-1) levels. Methods: A total of 30 untreated overt hyperthyroidism patients, 17 euthyroid congenital hypothyroidism children, and age- and sex-matched controls were enrolled. Levels of GLP-1, insulin, glucose, and homeostasis model assessment (HOMA-IR) were measured and evaluated. Results: Fasting GLP-1, blood glucose, insulin, and HOMR-IR levels were higher in patients with overt hyperthyroidism than in controls (p=0.030, p=0.008, p=0.004, p=0.037, respectively). These parameters in euthyroid hypothyroidism were similar to the controls. In euthyroid congenital hypothyroidism and overt hyperthyroidism patients, serum GLP-1 levels were not correlated with thyroid hormone, blood glucose, insulin, and HOMR-IR. Conclusions: Fasting GLP-1 levels in the peripheral circulation were significantly increased in overt hyperthyroidism, however, they were no different in euthyroid congenital hypothyroidism.

Aim: To investigate the perinatal complications and risk of thyroid dysfunction at early childhood of Graves’ disease (GD) mothers with euthyroidism (EU) or subclinical hyperthyroidism (sHT) during pregnancy. Method: One hundred and twenty-three pregnant women with GD were recruited. They were all in euthyroidism with treatment of anti-thyroid drugs (ATDs) before pregnancy. All the pregnant GD women maintained EU (n=55) or sHT (n=68) by using ATDs. Sixty randomly selected, age-matched healthy pregnant women (non-GD control) were included. The prenatal and newborn data were collected and analyzed. Toddlers of GD mothers (n=45) and non-GD healthy mothers (n=36) were also recruited for thyroid function and growth assessments. Results: Newborns of mothers with GD had significantly higher complications than those of non-GD mothers. The percent of perinatal complications were 5.0%, 30.9% and 32.3% in the control, EU (vs. control, p<0.001), and sHT (vs. control, p<0.001) groups, respectively. There were no differences between the women continuing low doses of ATDs at the start of pregnancy and the women who stopped receiving ATDs at the start of pregnancy. Toddlers’ serum levels of FT3, FT4, anti-thyroglobulin antibody, and anti-thyroid peroxidase antibody were significantly higher than those of non-GD mothers (all p<0.05). Conclusion: Pregnancy with GD significantly increases the perinatal complications even with EU. The continued use of ATDs at the start of pregnancy does not give an increased risk of perinatal complications in GD mothers. Maternal GD may also induce a higher risk of autoimmue thyroid dysfunction among offspring at early childhood.

Aim: Cranial diabetes insipidus (CDI) is rare in infants with no guidelines on its management. We describe the first case series, characterizing the clinical features and treatment challenges. Method: Retrospective case note review of infants diagnosed with CDI between April 1992 and February 2011. Results: Nineteen infants (52% male) were identified. Eight were born preterm. Median (range) age at diagnosis was 24 days (5–300); preterm babies were younger at diagnosis (21 vs. 46 days). In 58% (11/19) of infants, hypernatraemia was discovered incidentally. In 37% of cases there was associated midline anomalies, however, only four patients (21%) had absent posterior pituitary signal on a magnetic resonance imaging brain scan. The most frequent (5/19) underlying diagnosis was septo-optic dysplasia. Eight patients had isolated CDI and 11 had multiple pituitary hormone deficiencies. Isolated CDI tended to be more common in preterm, compared to term babies (p=0.11). Des-amino arginine vasopressin (DDAVP) was administered intranasally in eight and orally in 11 infants. Plasma sodium nadir following DDAVP administration was lower following intranasal compared to an oral route of administration (median: 128 vs. 133 mmol/L, p=0.022). No cases resolved on follow-up. Conclusions: CDI in infants is often diagnosed incidentally. Aetiology, clinical, and imaging features are very variable, with some differences between preterm and term infants. Oral DDAVP appears to be superior to intranasal with less pronounced serum sodium fluctuations.

Background: Central diabetes insipidus (DI) is a rare disorder in children caused by a deficiency of antidiuretic hormone arginine (vasopressin). Desmopressin is the first line agent in management of central DI. However, one of the side effects of desmopressin is water intoxication and hyponatraemia. This study reviews the patterns of desmopressin use and side effects in our institution. Methods: Retrospective chart review of all patients with central DI followed up in one tertiary centre between 1 January 2008 and 31 December 2010. Results: Forty-one patients (22 males and 19 females) were included. Twelve patients (29.3%) had congenital and 29 patients (70.7%) had acquired DI, mostly as a result of intracranial tumours. Thirty-six (87.8%) patients were on oral desmopressin and the remaining on nasal formulation. The median oral dose was 9.5 (4.2–17.0) μg/kg/day with median frequency of 2.5 (2–3). The median nasal dose was 0.7 (0.4–1.4) μg/kg/day with median frequency of 2.0 (2–3.5). Fourteen patients (34.1%) were switched from nasal to oral desmopressin with the median dose conversion factor of 20.1 (10.7–31.8). Forty percent of patients on nasal desmopressin experienced hypo/hypernatraemia compared to 18.1% on oral, however, there were no significance difference between standardized hypo/hypernatraemia episodes per treatment year. Conclusions: Oral desmopressin is used in the majority of our patients including infants and toddlers. There is wide inter-individual variation in dose requirement and dosing intervals. Management of central diabetes insipidus remains a challenge in adipsic patients and in young children during intercurrent illness regardless of the desmopressin formulation.

Background: Routine surveillance would be valuable for vitamin D deficiency as symptomatic vitamin D deficiency may be common in Scotland. Aim: To assess the effectiveness of an electronic surveillance system to determine the current incidence of hospital-based presentation of childhood vitamin D deficiency in Scotland. Methods: Active surveillance was performed for 2 years as part of an electronic web-based surveillance programme by the Scottish Paediatric Surveillance Unit. Notifications were followed by completion of a questionnaire. To further examine the validity of the system, cases with severe vitamin D deficiency in Glasgow and Edinburgh were identified from the regional laboratory and their clinical details were checked against those identified through the surveillance system. Results: Between September 2009 and August 2011, 109 cases of vitamin D deficiency were notified. The majority of cases (n=82) were reported in Glasgow with an annual incidence of 41 cases per year. Fourteen cases were reported in Edinburgh during the first year of the study and two cases during the second year. At the time of clinical diagnosis, the median age of the children was 2 years (range 3 months–16 years). Cross-validation of data showed that among symptomatic cases that had a measured serum vitamin D of <14 nmol/L, 89% of eligible cases had been reported in Glasgow and 33% of cases had been reported in Edinburgh. Conclusion: The incidence of vitamin D deficiency remains high in Scotland . An electronic surveillance system can provide data for studying the epidemiology of vitamin D deficiency but may underestimate the number of positive cases.

Aims: To assess the frequency and severity of diabetic ketoacidosis (DKA) at disease onset in children newly diagnosed with autoimmune type 1 diabetes (T1D) in Istanbul in the last decade. Also, to evaluate the potential contribution of the national diabetes awareness programme (NDAP) initiated in 2010. Methods: Four hundred and one consecutive children (mean±standard deviation, age 8.1±4.1 years) with a diagnosis of autoimmune T1D were evaluated retrospectively with respect to demographic, clinical, and laboratory data in relation to DKA at disease onset. The possible impact of NDAP on the rate of DKA at disease onset in the last 2 years was also evaluated by comparing the data related to the time intervals before and after the onset of the programme. The results were evaluated at 95% confidence interval and significance was granted for p≤0.05. Results: The overall frequency of DKA at disease onset was 44.2%, with a significant trend for decline in rate of DKA at disease onset in the last decade (p=0.0001). There were no significant differences in proportions of newly diagnosed T1D patients with severe or moderate DKA over time. Mean body mass index standard deviation score tended to increase in the last decade, but not significantly (p=0.09). When the time intervals before and after the onset of NDAP were evaluated, there was a more than two-fold decrease in rate of DKA (from 49.3% to 23.9%) (p<0.0001). Conclusions: The frequency of a DKA event at onset of T1D is still high in Istanbul children despite a decreasing trend in the last decade. NDAP may significantly contribute to the reduction in rate of DKA.

Background: The associations of 25-hydroxyvitamin D [25(OH)D], non-high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL), and related markers of early cardiovascular disease (CVD) are unclear in prepubertal children. Objective: To investigate the association of 25(OH)D with markers of CVD. The hypothesis was that 25(OH)D would vary inversely with non-HDL-C. Subjects and methods: A prospective cross-sectional study of children (n=45; 26 males, 19 females) of mean age 8.3±2.5 years to investigate the relationships between 25(OH)D and glucose, insulin, high-sensitivity C-reactive protein, and lipids. Vitamin D deficiency was defined as 25(OH)D <20 ng/mL; overweight as body mass index (BMI) ≥85th but <95th percentile; and obesity as BMI >95th percentile. Results: Twenty subjects (44.4%) had BMI <85%, and 25 had BMI of ≥85%. Eleven participants (24.4%) had 25(OH)D of <20 ng/mL, and 10 (22.2%) had 25(OH)D of >30 ng/mL. Patients with 25(OH)D of <20 ng/mL had significantly elevated non-HDL-C (136.08±44.66 vs. 109.88±28.25, p=0.025), total cholesterol (TC)/HDL ratio (3.89±1.20 vs. 3.21±0.83, p=0.042), and triglycerides (TG) (117.09±71.27 vs. 73.39±46.53, p=0.024), while those with 25(OH)D of >30 ng/mL had significantly lower non-HDL-C, TC/HDL, TG, and LDL (82.40±18.03 vs. 105.15±28.38, p=0.006). Multivariate analysis showed significant inverse correlations between 25(OH)D and non-HDL cholesterol (β=–0.337, p=0.043), and TC/HDL ratio (β=–0.339, p=0.028), and LDL (β=–0.359, p=0.016), after adjusting for age, race, sex, BMI, and seasonality. Conclusions: Vitamin D varied inversely with non-HDL, TC/HDL, and LDL. A 25(OH)D level of 30 ng/mL is associated with optimal cardioprotection in children.

Background: Factors such as vascular/neurological mechanisms, poor glycemic control, abnormalities in vitamin D/calcium, secondary hyperparathyroidism, and hypercalciuria have been blamed for the unfavorable effects of type 1 diabetes mellitus (type 1 DM) on bone health. In this present study, we aimed to evaluate the frequency of low bone mineral density (BMD) in children with type 1 DM. Method: Among 100 type 1 DM patients, a 25-hydroxy vitamin D level of <10 ng/mL was accepted as vitamin D deficiency and the level of 10–20 ng/dL was accepted as vitamin D insufficiency. BMD was measured, and Z-scores were evaluated according to adjusted Turkish standards. Participants with a Z-score of ≤–2 were defined as having low BMD; BMD between –2 and –1 were defined as being in the low range of normality; and values ≥–1 were accepted as normal. Results: The vitamin D deficiency and insufficiency ratios were 28% and 43%, respectively. Low BMD and BMD in the low range of normality were diagnosed in 10% and 25% of patients, respectively. There was no difference in vitamin D, parathormone, and metabolic control levels between three groups: with normal BMD, low BMD, and BMD in the low range of normality. BMD Z-scores were not different between the pubertal and prepubertal groups. Conclusion: Detailed evaluation should be performed for BMD in the follow-up of DM to prevent complications by decreasing related risks.

Background: Type 1 diabetes (T1D) management requires year-round adherence to treatment regimen. Holidays may present a challenge towards achieving good metabolic control. Objectives: Our aim was to investigate the effect of holidays on diabetes management of schoolchildren with T1D. Methods: Observational, case-crossover study of 45 schoolchildren, age range 7–19 years, mean 13.2±3.4 years, followed in a pediatric diabetes clinic. Subjects were stratified by age [<12 years (n=21), >12 years (n=24)] and treatment modality [insulin pump (n=29) or multiple daily injections (n=16)]. Data were downloaded from glucometers and insulin pumps during five non-weekend holidays and five subsequent school days. Results: The mean number of blood glucose (BG) readings was significantly lower (4.4±1.9 vs. 4.8±1.9, p<0.01) and mean BG marginally higher (11.4±2.7 vs. 10.7±3.1 mmol/L, p=0.1) during holidays than during school days in the entire cohort. Children were significantly more adherent to diabetes management than adolescents as expressed by lower mean glycated hemoglobin level (7.7±0.8% vs. 8.6±1.4%, p<0.05), more BG readings per day (p<0.001) and lower mean BG on holidays (p<0.05) and on schooldays (p<0.01). In pump users, no difference in the mean number of boluses per day and mean insulin units per kilogram per day was observed between holidays and school days. Conclusions: The management of school-aged children with T1D during holidays was worse than during school days; these finding were more pronounced in adolescents. The diabetes team should be aware of suboptimal therapy during holidays and should consider intervention programs in attempts to educate patients accordingly.

Body mass and anti-pancreatic antibody status potentially influences the presentation of diabetes in children. We hypothesized that anti-pancreatic auto-antibody positive patients with new onset diabetes would have lower levels of insulin and C-peptide at presentation, and hence higher HbA1c. Records of children with new onset diabetes self-identified as African American were retrospectively analyzed. Patients were under 19 years of age. Anti-GAD65 antibody titer, HbA1c, blood glucose, insulin and C-peptide levels were drawn at the time of diagnosis. Patients were classified as antibody positive if anti-GAD65 was ≥0.5. HbA1c, insulin and C-peptide levels were considered as dependent variables in statistical models that included auto-antibody status, gender, age, body mass index z score (BMI-z score), and blood glucose as independent covariates. Records of 61 African-American children were available for analysis. There was no statistical association of auto-antibody status or initial clinical diagnosis with HbA1c, insulin or C-peptide level. BMI-z score was strongly associated with insulin (p=0.0006) and C-peptide (p<0.0001) levels. In general, higher BMI-z score, female gender and older age were associated with higher C-peptide levels. Although potentially helpful in eventually determining etiology, pancreatic auto-antibody levels do not have an association with HbA1c, insulin or C-peptide levels in African-American children with new onset diabetes. BMI-z score had the most robust association with insulin and C-peptide levels at presentation.

Background: It is poorly understood whether dipeptidyl peptidase 4 (DPP4) activity is altered and how DPP4 contributes to glycemic control in patients with type 1 diabetes mellitus (T1DM). Aim: The aim of this study was to measure serum DPP4 activity and to assess its relationships to metabolic variables in T1DM children. Methods: Serum DPP4 activity was determined using a fluorometric assay in 43 T1DM and 26 control children. Results: Serum DPP4 activity was significantly higher in T1DM children than in controls (3.57±0.99 vs. 2.67±0.77 U/mL, p<0.001). In the T1DM children, DPP4 activity was not correlated with HbA 1c , blood glucose, or diabetes duration. A significant negative correlation was found between DPP4 activity and serum adiponectin levels in the T1DM group (r=–0.35, p<0.05). Conclusions: Serum DPP4 activity was increased in the T1DM children, whereas it was not associated with glycemic control. Given the negative correlation between serum DPP4 and adiponectin levels, further investigations are warranted to elucidate the role of DPP4 on insulin sensitivity in T1DM children.

Background: We previously demonstrated that children with Type 1 Diabetes Mellitus (T1DM) may have transiently elevated tissue transglutaminase antibodies (TTG) on a gluten-containing diet. This study aimed to examine if the presence of autoantibodies in newly diagnosed T1DM differs between patients with celiac disease and those with transient celiac serology. Methods: Forty children were identified who had been diagnosed with T1DM between 2003 and 2009 and who had elevated serum IgA-TTG antibody levels at diagnosis. Blood samples were collected for measurement of insulin (IA-2A) antibodies, islet cell antigen (ICA) antibodies, glutamic acid decarboxylase (GAD) antibodies, thyroglobulin (TgAb) antibodies, and thyroid peroxidase (TPO) antibodies. Children diagnosed with celiac disease (CD; group 1, n=23) and children in whom TTG antibody levels spontaneously normalized over time (group 2, n=17) were compared. Results: No significant differences in positivity rates between groups 1 and 2 were found for any of the autoantibodies tested. The respective findings were as follows: IA-2A 50% and 47.1% (p=0.855); ICA 77.3% and 76.5% (p=0.953); GAD 27.3% and 52.9% (p=0.102). Thyroid antibodies were found positive in a limited number of patients: TgAb 4.5% and 11.8%; TPO 4.5% and 11.8%. In addition, antibody titer levels did not differ significantly for all autoantibodies. Difference in occurrence of clinical or subclinical thyroid disease did not reach significance (4.3% vs. 29.4%; p=0.07). Age was positively correlated with the presence of thyroglobulin and thyroid peroxidase antibodies, and negatively correlated with the presence of insulin antibody. Conclusion: Neither the number of concomitant autoantibodies nor their titers in newly diagnosed T1DM differed between patients with proven CD and those with transient TTG serology.

Objective: To assess the user-friendliness of the Norditropin FlexPro (Novo Nordisk A/S, Bagsvaerd, Denmark), a newly developed growth hormone (GH) injection pen. Methods: This study consisted of a single-center, single-arm, open-label, questionnaire based survey of patients undergoing GH treatment for diverse indications who were scheduled to switch from the formerly used device Norditropin NordiFlex (Novo Nordisk A/S) to the FlexPro and evaluate each device’s usability. Results: A total of 82 patients participated in the study. Compared to the NordiFlex, the FlexPro was regarded as easier to grip, easier to hold during injection, and more stable during injection. The degree of pain at insertion perceived by the patient and the patient’s fear of injection were significantly decreased when using the FlexPro, and 81% of the respondents selected the FlexPro as the more preferable device. Conclusions: The FlexPro was more user-friendly than the NordiFlex. Perception of pain at insertion and fear of injection were lessened by using the FlexPro.

Aim: To investigate the association between cognitive impairment and gray/white matter volume abnormalities in pediatric patients with Turner syndrome (TS) presenting with various karyotypes. Methods: In the present study, 21 pediatric patients with TS and the 45,X karyotype, 24 pediatric patients with TS and other karyotypes, and 20 normal healthy controls, underwent the Wechsler intelligence test, behavioral testing, and a 3.0T magnetic resonance (MR) scan. Whole-brain high-resolution T1-weighted images were processed with SPM8 software and analyzed using voxel-based morphometry (VBM); differences in gray/white matter volume between the TS groups and healthy controls were compared using analysis of covariance. Results: Pediatric patients in both TS groups had significantly lower IQ scores compared to the normal controls (p<0.05). Furthermore, both TS groups scored significantly less than the normal controls in various composite tests of cognitive function, including verbal comprehension, perceptual reasoning, working memory, and processing speed (p<0.05). There were no significant differences between the two TS patient groups in terms of their scores for verbal comprehension, perceptual reasoning, working memory, and processing speed. However, they did display significant differences in the following tests: accuracy and reaction times in the executive control test, reaction times in the short-, middle-, and long-term attention test, and accuracy in the long-term attention test. Patients in the 45,X karyotype group displayed decreased gray matter volume in the bilateral cuneus, calcarine sulcus postcentral gyrus, right precuneus, superior parietal lobule, lingual gyrus, left precentral gyrus, and cingulate gyrus. However, gray matter volume was increased in the bilateral dorsal midbrain, orbital frontal gyrus, left insular lobe, superior temporal gyrus, inferior temporal gyrus, parahippocampal gyrus, cerebellum, posterior insular lobe, right caudate nucleus, putamen, and temporal pole. Patients with TS with other karyotypes exhibited decreased gray matter volume in the left precuneus, cingulate gyrus, right postcentral gyrus, supramarginal gyrus, angular gyrus, and cuneus; contrastingly, gray matter volume increased in both the epencephals, left caudate nucleus, superior temporal gyrus, right insular lobe, and temporal pole. All volume differences were statistically significant when compared with normal controls [familywise error (FWE)-corrected p<0.05]. With regard to the two TS groups, gray matter volume in the left hippocampus and left caudate nucleus was significantly decreased in the 45,X karyotype group compared to patients with TS with other karyotypes (FWE-corrected p<0.05); conversely, gray matter volume in the right supramarginal gyrus was increased in the 45,X karyotype group (FWE-corrected p<0.05). Conclusion: Pediatric patients with TS display a lower level of intelligence compared to healthy controls, this is complicated by verbal and non-verbal cognitive impairment. The neuropathological basis of such cognitive deficiencies may be as a result of abnormalities in gray matter development.

Aim: To assess prevalence of metabolic syndrome (MS) in urban Indian adolescents. MS in adolescents is a forerunner of diabetes mellitus and cardiovascular disease in adults, therefore, its identification provides an opportunity to intervene with lifestyle changes to prevent disease progression into adulthood. We randomly selected 900 adolescents (300 for each group) to participate in the study from a total of 15,101 adolescents (10–18 years) who were grouped as normal, overweight, and obese (total population). Methods: From the 900 adolescents, 695 consented to participate in the study and underwent a detailed anthropometric and biochemical evaluation, therefore, these adolescents constituted the study population. MS was defined by criteria proposed by the International Diabetes Federation (MS-IDF) and the Adult Treatment Panel (MS-ATP). The prevalence of MS in the study population was used to calculate the prevalence of MS in the total population based on the distribution of the different BMI categories in this larger sample (n=15,101). Results: Calculated prevalence of MS in urban Indian adolescents was 4.3% and 3.0% in the total population using MS-ATP and MS-IDF criteria, respectively. Among the study population, MS was higher in girls than boys (MS-ATP, G: 22.3% vs. B: 16.6%, p=0.03; MS-IDF, G: 20.5% vs. B: 13.5%, p=0.006). The most common component of MS- ATP and MS-IDF was central obesity (89.8% vs. 100.0%, p<0.00001), followed by hypertriglyceridemia (83.0% vs. 82.2%, p=0.35), low high density lipoprotein-cholesterol (71.1% vs. 71.2%, p=0.48), hypertension (44.4% vs. 44.9%, p=0.025), and dysglycemia (40.0% vs. 34.7%, p=0.94). The mean serum insulin levels and HOMA-IR progressively increased with the increasing number of components present in an individual. Conclusions: Metabolic syndrome is common in urban Indian overweight and obese adolescents.

Metabolic syndrome (MS) related to adult type 2 diabetes mellitus and cardiovascular disease is prevalent among obese children/adolescents. Genetic variants of the leptin-melanocortin system have been associated with components of MS. The aim of our study is to estimate the prevalence of MS (according to Cook’s criteria) in a Chilean cross-sectional sample of 259 obese children (47.1% girls, aged 6–12 years), and to assess the association between common genetic variants of leptin-melanocortin pathway genes ( LEP , LEPR , POMC , MC3R and MC4R ) with components of the MS using logistic regression. We observed an overall MS prevalence of 26.3% (32.2% in girls and 21.1% in boys) in obese Chilean children. No associations were detected between genetic variants of leptin-melanocortin genes and MS components. MS prevalence among our obese children sample is similar to those previously described in Chile, demonstrating the increased risk of diseases in adulthood that obese children carry.

Aim: Nonalcoholic fatty liver disease (NAFLD) is associated with inflammation and increased risk of atherosclerosis. Neopterin is regarded as a biochemical marker of cell-mediated immunity, which is secreted by monocytes and macrophages, mainly in response to interferon-gamma. The aim of the present study was to investigate the serum neopterin levels in obese adolescents and compare the neopterin levels in patients with and without NAFLD and also with healthy controls. The second aim of the study was to research the possible relationship between neopterin levels and adipokines (leptin, adiponectin, resistin, and ghrelin). Methods: Ninety-three obese adolescents (39 with NAFLD, 54 without NAFLD) and 55 healthy controls were enrolled in the study. Serum levels of neopterin and adipokines were measured with high-performance liquid chromatography and sandwich enzyme-linked immunosorbent assay, respectively. Results: Serum neopterin levels were significantly higher in patients with NAFLD (3.20±0.09 nmol/L) than in their healthy peers (2.91±0.08 nmol/L) (p=0.020). Neopterin levels were positively correlated with leptin levels in obese patients (r=0.380, p<0.001) and in the group comprising all individuals (r=0.206, p<0.05). There was no correlation between neopterin concentrations and relative weight, alanin aminotransferase, adiponectin, resistin, and ghrelin levels. Conclusion: The serum neopterin levels were significantly higher in obese adolescents with fatty liver disease compared to controls, and this may be related to increased cell-mediated immunity in fatty liver disease.

Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. Human chitotriosidase is a recently described fully active chitinase expressed by activated macrophages. Marked elevation of chitotriosidase activity was initially observed in plasma of patients with Gaucher disease. Subsequently, elevation was also observed in various lysosomal storage disorders such as fucosidosis, galactosialidosis and glycogen storage disease type IV. The aim of the present study was to evaluate plasma chitotriosidase activity in 19 children with glycogen storage disease type I. Plasma chitotriosidase levels were found to be significantly higher in children with GSD type I than healthy age-matched controls (21.3±16.4 vs. 12.3±8.9 nmol/h/mL, p=0.04). All the patients reported here presented with hepatomegaly. Our report expands the spectrum of disorders that should be included in the differential diagnosis of patients with increased plasma chitotriosidase activity, irrespective of the mechanisms involved.

Recent studies have demonstrated a role for calcium channel blocking agents in the treatment of persistent hyperinsulinemic hypoglycemia of newborns. We report a newborn infant with persistent hyperinsulinemic hypoglycemia whom we successfully treated with oral nifedipine alone after surgical therapies. A 4-day-old male infant was referred with intractable hypoglycemia and seziures. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20 mg/kg per minute. Persistent hyperinsulinemic hypoglycemia of newborn was diagnosed from an inappropriately raised plasma insulin concentration (44 mU/L) at the time of hypoglycemia. Medical treatments led to only a mild reduction in the intravenous glucose requirement; an 85–90% pancreatectomy was performed and histological “diffuse nesidioblastosis” was confirmed. However, despite all the medical treatments after the first pancreatectomy, the hyperinsulinemic hypoglycemia persisted and a second 95% pancreatectomy was performed. After the second pancreatectomy, persistent hyperinsulinemic hypoglycemia was treated with somatostatin and diazoxide, but led to no reduction in the intravenous glucose requirement. We report the case of an infant who had persistent hypoglycemia after two subtotal pancreatic resections but subsequently became normoglycemic on treatment with nifedipine (2 mg/kg per day). The patient was discharged home on oral nifedipine. Calcium channel blocking agents cuold be used with efficacy and safety in recurrent persistent hyperinsulinemic hypoglycemia.

Congenital hyperinsulinism (CHI) results from inappropriate excessive insulin secretion by the beta cells in the pancreas. A wide clinical spectrum of disease exists and a genetic diagnosis is now possible for approximately 50% of affected children. We describe a patient with atypical diffuse CHI caused by mosaic ABCC8 mutation inheritance, unmasked by paternal uniparental disomy. Hypoglycaemia persisted despite two subtotal pancreatectomies and trials of diazoxide and nifedipine were unsuccessful. Octreotide resulted in anaphylaxis, precluding its use. Continuous subcutaneous glucagon infusion was successful in restoring normoglycaemia and attenuating weight gain, with concomitant improvement of developmental milestones. No adverse effects have been encountered after >12 months of therapy. Administration problems (e.g., line crystallisation) may complicate continuous glucagon therapy; hence a practical description of infusion constitution is included. We recommend consideration of continuous subcutaneous glucagon infusion as a therapeutic option for persistent refractory hypoglycaemia in CHI.

Insulin autoimmune syndrome (IAS) or Hirata’s disease is a rare cause of hyperinsulinemic hypoglycemia. We report the case of a child with a mild, atypical presentation of IAS. A previously healthy girl, aged 7 years old, developed non-ketotic fasting hypoglycemia during treatment for pneumonia. Laboratory evaluation during hypoglycemia showed the following results: serum glucose, 32 mg/dL (1.8 mmol/L); insulin, 5.6 μIU/mL (38.9 pmol/L); C-peptide, 1.4 ng/mL (0.47 nmol/L); anti-insulin antibody, 6.2% (normal, <2.4%); absence of ketonuria; and positive glucagon stimulation test result. Search for mutation in genes ABCC8 , KCNJ11 , GLUD1 and MEN1 was negative. Human leukocyte antigen (HLA) typing was HLA-DRB1*1104 . Computed tomography scan of the abdomen showed a normal result. The patient evolved with spontaneous resolution of the hypoglycemia, within 30 days, with normalization of serum anti-insulin titers. The serum levels of insulin and anti-insulin antibodies in the patient of this report were not extremely high as previously reported. This novel, mild, or forme fruste presentation of IAS expands the previously reported spectrum of this disease.

A term neonate was diagnosed with septo-optic dysplasia (SOD) on the 11th day of life. The patient had hypernatremia, hypoglycemia, and hypothermia. The patient’s persistent hypothermia prompted a head ultrasound to examine for abnormalities of the central nervous system, which suggested an absent septum pellucidum. A subsequent brain magnetic resonance imaging confirmed an absent septum pellucidum, and coupled with pituitary dysfunction and bilateral optic nerve hypoplasia, the diagnosis of SOD was made. The authors argue that persistent hypothermia in a neonate may raise the index of suspicion for SOD and thereby facilitate an earlier diagnosis of SOD.

Background: Hyperthyroidism is rare in pre-school children. Untreated, it can have a profound effect on normal growth and development, particularly in the first 2 years of life. Although neurological manifestations of dysthyroid states are well known, specific expressive speech and language disorder as a presentation of hyperthyroidism is rarely documented Methods: Case reports of two children with hyperthyroidism presenting with speech and language delay. Results: We report two pre-school children with hyperthyroidism, who presented with expressive speech and language delay, and demonstrated a significant improvement in their language skills following treatment with anti-thyroid medication. Conclusions: Hyperthyroidism must be considered in all children presenting with speech and language difficulties, particularly expressive speech delay. Prompt recognition and early treatment are likely to improve outcome.

Lissencephaly is a rare brain malformation characterized by a smooth cerebral surface, thickened cortical mantle and microscopic evidence of incomplete neuronal migration. Association of congenital hypothyroidism with lissencephaly is seldom reported. We report a case of lissencephaly with congenital hypothyroidism.

Objective: X-linked hypophosphatemic (XLH) rickets is caused by inactivating mutations in the PHEX gene, which encodes a metalloprotease that cleaves small peptide hormone. So far there are only a few reports on XLH patients from China. In the present study, we report on six XLH patients from one family. A PHEX missense mutation was found in exon 22, and a literature review on the mutations of Chinese patients was undertaken. Case description: The family included six XLH patients with five females and one male (the proband). All the patients showed a low serum phosphorus, increased blood alkaline phosphatase and normal calcium levels. Mutation analysis revealed a PHEX mutation in exon 22 (c.2237G>A). In total, 15 PHEX mutations have been reported in Chinese populations at this time. Conclusion: These data extend the spectrum of mutations in the PHEX gene in Chinese populations.

Primary hyperparathyroidism (PHP) and myelofibrosis are rare entities in childhood. Myelofibrosis secondary to PHP is also extremely rare. We report a 15-year-old boy presented with generalized weakness, vomiting, and pallor. A parathyroid adenoma was detected on the left distal parathyroid gland. PHP was diagnosed together with hepatosplenomegaly and pancytopenia. Bone marrow biopsy revealed grade 3–4 reticulin fibrosis. As early as 2 months after the left distal parathyroidectomy, hematologic parameters improved without any other intervention. His liver and spleen also gradually decreased in size. We concluded that the pancytopenia was as a result of myelofibrosis from PHP.

Objectives: Camurati-Engelmann disease (CED) is a rare form of progressive diaphyseal dysplasia as a result of mutations in the transforming growth factor gene TGFbeta1 on chromosome 19q13.1-q13.3. Endocrine complications such as osteoporosis, vitamin D deficiency, delayed puberty, and hypogonadotrophic hypogonadism may be present. Methods: Genetic analysis of the TGFbeta1 gene revealed a heterozygous missense mutation p.R218C in exon 4 of chromosome 19q13.1-q13.3 in a 14-year-old girl who presented with typical symptoms of CED, hyperprolactinaemia, and menstrual irregularity. Results: The patient responded well to prednisone 5 mg/kg/day, as well as calcium and vitamin D supplements. Conclusions: The role of p.R218C in TGFbeta1 on the mechanism of the disease, and the complications of it in bones and endocrine glands, remains unclear. Early recognition as well as a detailed understanding of the pathogenesis of the disease are important for future treatment options and a better quality of life of such patients.

Systemic pseudohypoaldosteronism type 1 (PHA1) is characterized by excessive salt loss from the renal tubulus, colon, sweat and salivary glands. Here we present a case of systemic PHA1 whose genetic analysis revealed a homozygous splicing mutation in intron 4 of SCNN1A (c.684+2 T>A) and discuss with the patient’s phenotype. Previously described systemic PHA cases show varying degrees of severity dependent on the mutation. Most of the SCNN1A gene mutations present with a severe phenotype. The long-term follow-up and phenotype of the two reported cases with splicing mutation of the SCNN1A gene are unknown. Our case, with a new splicing mutation of SCNN1A , presented with a severe phenotype in the neonatal period. Since then she has been well without any hospitalization and respiratory illness. Her requirement for medication also decreased gradually. After early infancy she presented a mild systemic PHA1 phenotype up to the age of 39 months. In conclusion, the mutation in the patient is located at the splicing site and is definitely a new and pathogenic one, and the phenotype of the patient was milder as observed in a patient with missense mutation.

Prader-Willi syndrome (PWS) is characterized by infantile lethargy and hypotonia causing poor feeding and failure to thrive, childhood obesity, short stature, and hypogonadism. The complex phenotype is most probably caused by a hypothalamic dysfunction that is responsible for the hormonal dysfunction. The resulting hypogonadism in PWS causes incomplete, delayed, and sometimes disordered pubertal development. Precocious puberty is very rare in PWS. We report the case of a girl with PWS who was diagnosed with idiopathic precocious puberty and was treated with gonadotropin-releasing hormone analog.

In children with sickle cell disease, reports of type 1 diabetes mellitus (T1D) are extremely rare. Several studies failed to show the co-existence of the two conditions. In the few cases reported, the diagnosis has been made solely based on the clinical presentation. Here we report the case of an adolescent with sickle cell anemia who presented with hyperglycemia and positive T1D-specific auto-antibodies.

Objective : An obesity risk allele at the NEGR1 locus was shown to be associated with weight regain after a lifestyle intervention in obese adults. Independent confirmation and studies in children are lacking. Therefore, we analyzed the impact of this and 11 additional obesity susceptibility loci on weight regain after a lifestyle intervention in overweight children. Design and Methods: We longitudinally analyzed the changes in weight status as body mass index standard deviation score (BMI-SDS) in 282 overweight children (10.6±2.5 years, 47% male, BMI 27.1±3.9 kg/m 2 ) both at the end of a 1-year lifestyle intervention and at 1 year after the end of intervention. We genotyped obesity risk single nucleotide polymorphisms (SNPs) derived from genome-wide association studies in or in proximity to the following genes: NEGR1, TNKS, SDCCAG8, FTO, MC4R, TMEM18, PTER, MTCH2, SH2B1, MAF, NPC1, and KCTD15 . Results: The children reduced their BMI-SDS (–0.28±0.35; p<0.001) during intervention and increased their BMI-SDS between the end of intervention and 1 year later (+0.05±0.36; p=0.027). None of the SNPs including NEGR1 was related significantly to weight regain. Conclusions: We found no evidence for effects of any of the GWAS-based obesity marker alleles on weight regain in the course of 1 year after an intervention.